Silent Cerebral Infarct (SCI) is the most common cause of severe neurological disease in children with sickle cell anemia, occurring in 22% of this population prior to their 18th birthday. The overall goal of this trial is to determine whether blood transfusion therapy will decrease further neurologic morbidity in children with Silent Cerebral Infarcts and, if so, the magnitude of this benefit. We propose a multi-center, randomized trial with 22 Clinical Sites, a Clinical Coordinating Center, and a Statistical Coordinating Center (see accompanying R01--PI Michael Terrin, MD, MPH) to test the following hypothesis: Prophylactic blood transfusion therapy in children with Silent Cerebral Infarcts will result in at least an 86% reduction in the rate of subsequent overt strokes or new cerebral infarcts, as defined by the MRI of the brain. The intervention is blood transfusion therapy vs. observation, with a goal to keep the maximum hemoglobin-S concentration less than 30% in the transfused patients. Approximately 3,020 children with Sickle Cell Anemia, greater than 6 years of age and less than 13 years of age, will be eligible for screening evaluations. Among this group of eligible patients, approximately 1,880 children will be asked to participate and will receive MRIs of the brain. In this group, we estimate that 376 children (20%) will have Silent Cerebral Infarcts, among whom 38 children (10%) will have an elevated TCD measurement ( 200 cm./sec. and will not be eligible for the study. The remaining 338 children will be eligible for random allocation to either observation or blood transfusion therapy. Based on a 60% parent, and a child acceptance rate among children with Silent Cerebral Infarcts, a study size of 203 participants (at least 101 in each treatment assignment) ensures 90% power to detect the effect necessary to make transfusion therapy worth recommending (86% reduction), after accounting for 10% drop-out and 20% crossover rates. The standardization of the trial will occur during the first six months, enrollment for 24 months, and the intervention for 36 months. Twelve months after enrollment, each patient will receive a MRI and TCD. Each study participant will receive MRI and cognitive assessment at study exit (month 36 after enrollment). The primary aim of this trial is to determine the effectiveness of blood transfusion therapy for the prevention of stroke, or new Silent Cerebral Infarct assessed by the MRI of the brain. The secondary aims of this trial are determining whether: 1) prophylactic blood transfusion therapy will limit further decline in general intellectual abilities; and 2) the overall benefits of blood transfusion therapy for Silent Cerebral Infarcts outweigh risks associated with this therapy in a formal risk-benefit analysis. We anticipate results of this study could lead to a change in standard care practices for children affected with both sickle cell Disease and silent cerebral Infarcts.